ABSTRACT.    High Mobility Group Box proteins (HMGB) are highly conserved throughout evolution and act as nuclear architectural factors involved in chromatin remodelling. In addition, these factors are released from cells and as pro-inflammatory cytokines participate to diverse human pathogenesis. In Plasmodium, 4 HMGB proteins were predicted including those we named HMGB1 and HMGB2, highly conserved in Plasmodium species. They are small proteins containing one HMG-box closely related to the metazoan box B and comprising a TNF activating domain. In vitro analyses established that Plasmodium falciparum proteins PfHMGB1 and PfHMGB2 interact with distorted DNA structures, are able to bend linear DNA and are probably involved in epigenetic regulation. The proteins were detected mainly in the nucleus throughout erythrocytic parasite development; PfHMGB1 preferentially expressed in asexual stages whereas PfHMGB2 mainly detected in gametocytes. In addition, PfHMGB1 and PfHMGB2 are released from parasitized erythrocytes and might elicit a potential pro-inflammatory activity. Ex vivo analyses evaluated this potential role on activation of quiescent monocytes and TNF alpha production. The implication of Plasmodium berghei PbHMGB1 and murine HMGB was investigated in a murine model of cerebral malaria, where C57BL/6 mice are infected with P. berghei ANKA. In presence of antibodies raised against PbHMGB1, 30 % survival was observed when compared to infected mice dying from cerebral malaria within 6 days. Expression of Plasmodium and murine HMGB transcripts as well as transcripts of cytokines and adhesion molecules are analysed in brains of infected mice and compared to those of the control non-infected, and PbHMGB1 preimmunized infected mice.